OVERALL SUMMARY The Dana Farber/Harvard Cancer Center (DF/HCC) multiple myeloma (MM) SPORE renewal application consists of 3 Research Projects and 3 Cores, as well as the Career Enhancement and Developmental Research Programs. During the previous funding period, we have capitalized on the complementary strengths of the research, clinical expertise, and facilities of the Harvard affiliated institutions including Dana Farber Cancer Institute, Massachusetts General Hospital, Harvard Medical School, and Harvard School of Public Health. We have successfully translated multiple novel agents from the bench to the bedside and FDA approval for treatment of MM. In this SPORE renewal application one new project has evolved from prior Developmental Projects, and three investigators who are now Co-PI's have previously received Developmental Research or Career Enhancement Awards. This new project focuses on developing novel therapeutic strategies in Waldenstrom's macroglobulinemia, a plasma cell disorder with unique biology. The group as a whole has a long-term commitment to translational MM research, with the necessary administrative, basic science, and clinical infrastructure. At our well established centers, more than 750 new patients with MM are evaluated annually, as well as 10,000 outpatient visits for established patients with plasma cell dyscrasias. The spectrum of diseases evaluated spans from monoclonal gammopathy of unclear significance to plasma cell leukemia to Waldenstrom's macroglobulinemia. Our center has appropriate scientific and institutional review boards, as well as protocol audit and quality control centers, to conduct cutting-edge translational research. This large combined patient base assures rapid accrual and evaluation of the therapeutic efficacy of novel agents identified in this program with over 40 active protocols. Success of both the preclinical and clinical components of this Program is dependent upon synergy and communication between these investigators which is assured by the access to all the Principal Investigators to the preclinical data generated in joint research efforts. Currently there is systematic quality-controlled exchange of bone marrow and blood samples for correlative basic laboratory studies. The overall goal of this DF/HCC myeloma SPORE is to take advantage of our increased understanding of the genetic and molecular basis of multiple myeloma and Waldenstrom's macroglobulinemia to develop novel, effective therapeutic strategies for patients. The translational nature of the SPORE is highlighted by the fact that most of our projects have emanated from clinical studies from the outset. Specific Projects are: (1) Therapeutically Targeting Ubiquitin Receptors in Multiple Myeloma; (2) Targeting AP Nuclease, a Mediator of Genomic Instability in MM; (3) Targeting Mutated MYD88 Signaling in WM; An Administration Communication and Planning Core; as well as Tissue Core 1 and Biostatistics and Bioinformatics Core 2, will continue to support the program. This Program therefore helps move rational novel targeted therapies from the laboratory to clinical protocols to improve patient outcome in MM.